Natural and Synthetic Compounds, Swords for Glioblastoma Therapy: From Tumor to Its Microenvironment

Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, which remains difficult to treat because of extensive intratumoral heterogeneity, intrinsic and acquired treatment resistance, a profoundly immunosuppressive tumor microenvironment (TME), and restricted drug delivery across the blood–brain barrier (BBB). Owing to their relatively low molecular mass, potential for BBB penetration, and ability to modulate multiple targets, natural and synthetic compounds have attracted increasing interest as candidates for GBM treatment. This narrative review summarizes the mechanisms by which naturally derived compounds—including saponins, flavonoids, and sesquiterpene lactones—and synthetic small molecules exert anti-GBM effects on tumor and the TME. Their reported actions include suppressing key prosurvival pathways, such as the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa B (NF-κB), and mutant p53 signaling; activating regulated cell-death processes, including apoptosis, pyroptosis, and parthanatos, as well as autophagy-associated cell death; and remodeling the tumor immune milieu to promote CD8⁺ T-cell infiltration. In preclinical models, some of these agents also overcome temozolomide (TMZ) resistance and resensitize glioma stem cells (GSCs) to chemotherapy or radiotherapy. Future studies should prioritize molecularly informed patient stratification, rational combination strategies, and advanced nanocarrier-mediated delivery platforms to facilitate the clinical translation of small-molecule therapeutics for GBM.